1. Technical Field
The present disclosure relates to polymeric compositions used in medicine and, more particularly, to liquid polymer mixtures which are capable of undergoing macrophase separation in aqueous environments to form bioabsorbable implants.
2. Background of Related Art
Bioabsorbable polymers are well-known for use in medicine. Typical formulations of such polymers are used in wound closure and wound repair, e.g., absorbable sutures, absorbable staples, absorbable osteosynthesis screws, absorbable hernia repair mesh and the like. Bioabsorbable polymers are also used for degradable drug delivery devices. The above items are ordinarily manufactured, e.g., by molding, drawing or spinning into the preformed final product which is then used as indicated by a surgeon.
In certain circumstances customized implant forms and shapes are necessary that are not provided by preformed shapes. Wound dressings or adhesion barriers of unique shape are frequently applied to irregularly shaped surfaces. The surgeon may need to cut the adhesion barrier or wound dressing to provide the appropriate shape. Unfortunately, such manipulations by the surgeon may be time consuming and, despite care and skill, the dressing or barrier may not adequately conform and/or adhere to the underlying tissue terrain.
Small voids or cavities, e.g., a periodontal pocket, present unique problems relating to treatment of infection or trauma. Ideally, treatment of the periodontium involves preventing or eradicating infection by cleaning and/or antimicrobial therapy and, in certain cases, barrier formation to aid restoration of normal healthy periodontium tissue. Antimicrobial therapy usually involves systemic and/or local administration of antimicrobial drugs. Systemic administration is associated with certain disadvantages, e.g., the time needed to reach effective blood levels at the target site and potential fungal superinfection during antibiotic therapy. Moreover, patient compliance in adhering to an oral dosage regimen is often problematic. Maintaining effective drug levels in a periodontal pocket is difficult in connection with local administration of drugs since dosage forms that do not provide sustained or controlled release are quickly washed away by aqueous secretions in the mouth. Periodontal pockets are often difficult to access without large-scale mutilation of surrounding periodontium. Preformed sustained or controlled release drug delivery systems applied within the mouth, but outside a damaged periodontal pocket may fail to provide effective spatial placement of the drug due to crevicular plasma flow preventing contact of the drug with the target locus. Ideally, therapy should be directed to spatial placement and sustained and/or controlled temporal delivery directly within the affected periodontal pocket. An irregularly shaped periodontal pocket that is difficult to access is not easily amendable to receiving a preformed drug delivery device, i.e., the device would be difficult to insert and not adequately provide proper or complete spatial placement over terrain within the cavity.
Natural repair or restoration of the periodontium involves migration and replacement of ligament cells, epithelial cells and fibroblasts in the injured area. Ligament cells provide a strong bond for teeth and other hard tissue structures. The presence of a predominant amount of cells which are not soft connective tissue cells, e.g., epithelial cells, at an injury repair site creates a soft or weak bond to surrounding hard tissue. A barrier to epithelial cells and fibroblasts allows a predominance of ligament cells to populate the injured area and creation of a strong bond to surrounding hard tissues. As with drug delivery devices, a preformed barrier would not fit easily into and conform to the complex geometry of a target location to provide an effective barrier to epithelial cells and fibroblast migration.
As a consequence, attempts have been made to formulate surgical aids that provide in-situ forming drug delivery devices, barriers and dressings. U.S Pat. No. 4,911,926 describes aqueous and non-aqueous compositions made of polyoxyalkylene block copolymers which form gels at mammalian body temperatures for use in reducing post-operative adhesion formation following surgery to the peritoneal or pleural cavities. Other gel forming compositions have been developed for preventing adhesions, e.g., U.S. Pat. Nos. 5,093,319 (chitin derivative soluble in aqueous solutions containing dilute acids), 5,080,893 (aqueous solutions of hydrophilic polymeric materials of high molecular weight), 4,994,277 (xanthan gum), 4,532,134 (chitosan coagulum), and 4,141,973 (hyaluronic acid).
Another approach to making implants involves dissolving a polymer in monomeric solvent to provide a desirable form of the polymer. Examples of such monomeric solvents include halogenated alkanes, ketones or aromatic hydrocarbons. The resulting mixture is applied to a desired substrate and a solid film or coating is produced when the solvent evaporates. However, concerns about the fugacity and/or toxicity of such monomeric organic solvents and the danger associated with explosion, or absorption by localized viable tissue has created a distinct need for less harmful substrates.
Certain biodegradable in-situ forming implants and methods of forming them are described in U.S. Patent Nos. 5,278,201, 5,077,049 and 4,938,763. As described therein, a thermoplastic system involves dissolving a solid, linear-chain, water-insoluble biodegradable polymer in a monomeric solvent to form a liquid solution. After the polymer solution is placed into the body, the monomeric solvent dissipates or diffuses away from the polymer, leaving the polymer to coagulate or solidify, leaving a solid structure. A drug may be added to the polymer solution to form a homogeneous solution or be dispersed to form a suspension or dispersion of drug within the polymeric solution. The thermoplastic system may be placed into a syringe and injected into the body. U.S. Pat. No. 5,077,049 describes the thermoplastic system for use in regenerating the periodontium.
U.S. Pat. No. 5,236,355 is directed to an apparatus for the treatment of peridontal disease. As described therein, sustained release compositions for the local administration of a therapeutic are administered as a plurality of dry, discrete microparticles of at least one therapeutic agent dispersed in a matrix made of a biocompatable and biodegradable polymer. The microencapsulated compositions may be produced by a phase separation process which employs silicone fluids as hardening agents. Methylene chloride is used to disolve the biodegradable polymer prior to mixing with the silicone.
Unfortunately, the use of monomeric solvents as described above leads to irritation of surrounding tissue and nerve endings since monomeric solvents are absorbed quickly and cause localized hypertonicity and tissue dehydration. The result is pain in the area of implant which can be associated with tissue necrosis. Moreover rapid dissipation of the monomeric solvent leads to shrinkage of the implant and non-uniform changes in its dimensions due to rapid uneven precipitation. Consequently, there is a need for in-situ forming implants that overcome the above described drawbacks. Such in-situ forming implants would present a distinct advantage over preformed implants and the above mentioned irritating in-situ forming implants.